An urban perinatal health programme of strategies to improve perinatal health

Promotion of a healthy pregnancy is a top priority of the health care policy in many European countries. Perinatal mortality is an important indicator of the success of this policy. Recently, it was shown that the Netherlands has relatively high perinatal death rates when compared to other European countries. This is in particular true for large cities where perinatal mortality rates are 20-50% higher than elsewhere. Consequently in the Netherlands, there is heated debate on how to tackle these problems. Without the introduction of measures throughout the entire perinatal health care chain, pregnancy outcomes are difficult to improve. With the support of health care professionals, the City of Rotterdam and the Erasmus University Medical Centre have taken the initiative to develop an urban perinatal health programme called 'Ready for a Baby'. The main objective of this municipal 10-year programme is to improve perinatal health and to reduce perinatal mortality in all districts to at least the current national average of 10 per 1000. Key elements are the understanding of the mechanisms of the large health differences between women living in deprived and nondeprived urban areas. Risk guided care, orientation towards shared-care and improvement of collaborations between health care professionals shapes the interventions that are being developed. Major attention is given to the development of methods to improve risk-selection before and during pregnancy and methods to reach low-educated and immigrant groups

The Arab Human Rights Position in the Light of International Law

The depressing circumstances of contemporary political life in the Arab world has led me to make this study, aiming to examine the position of Arab countries in the light of their obligations under international law, by analysis of the instruments of international human rights law which recognise and aim to protect certain rights and freedoms. I intend to examine the status of those instruments whether at the national, regional or international level. I will examine the Arab governments' legal position according to international institutions and the instruments, in particular, to what extent they recognize them and subject to what restrictions. I will review whether those rules and instruments are acceptable to all the Arabs and if Arab states have made relevant reservations or derogations. The purpose of this analysis is to assess the extent to which the Arab individual's rights and freedoms are protected, and the legal remedy available to him, in the light of international human rights law, as well as in the regional and national provisions which aim to achieve protection of human rights. I examine different concepts of human rights and other international issues related to them, including the Islamic concept of international law and human rights, as in the conte.J1lporary Arab world religion continues to be a significant factor

Fully fabric high impedance surface-enabled antenna for wearable medical applications

The compact and robust high-impedance surface (HIS) integrated with the antenna is designed to operate at a frequency of 2.45 GHz for wearable applications. They are made of highly flexible fabric material. The overall size is $45\times \,\,45\times 2.4$ mm3 which equivalent to $0.37\lambda \text{o}\times 0.37\lambda \text{o}\times 0.02$ mm3. The value of using HIS lies in protecting the human body from harmful radiation and maintaining the performance of the antenna, which may be affected by the high conductivity of the human body. Besides, setting the antenna on the human body by itself detunes the frequency, but by adding HIS, it becomes robust and efficient for body loading and deformation. Integrated antenna with HIS demonstrates excellent performance, such as a gain of 7.47 dBi, efficiency of 71.8% and FBR of 10.8 dB. It also reduces the SAR below safety limits. The reduction is more than 95%. Therefore, the presented design was considered suitable for wearable applications. Further study was also performed to show the useful of placing antenna over HIS compared to the use of perfect electric conductor (PEC). The integrated design was also investigated with the worst case of varying the permittivity of body equivalent model which shows excellent performance in term of reflection coefficient and SAR levels. Hence, the integrated antenna with HIS is mechanically robust to human body tissue loading, and it is highly appropriate for body-worn applications

Immunologic Predictors for Clinical Responses During Immune Checkpoint Blockade in Patients With Myelodysplastic Syndromes

PURPOSE: The aim of this study is to determine immune-related biomarkers to predict effective antitumor immunity in myelodysplastic syndrome (MDS) during immunotherapy (IMT, αCTLA-4, and/or αPD-1 antibodies) and/or hypomethylating agent (HMA). EXPERIMENTAL DESIGN: Peripheral blood samples from 55 patients with MDS were assessed for immune subsets, T-cell receptor (TCR) repertoire, mutations in 295 acute myeloid leukemia (AML)/MDS-related genes, and immune-related gene expression profiling before and after the first treatment. RESULTS: Clinical responders treated with IMT ± HMA but not HMA alone showed a significant expansion of central memory (CM) CD8+ T cells, diverse TCRβ repertoire pretreatment with increased clonality and emergence of novel clones after the initial treatment, and a higher mutation burden pretreatment with subsequent reduction posttreatment. Autophagy, TGFβ, and Th1 differentiation pathways were the most downregulated in nonresponders after treatment, while upregulated in responders. Finally, CTLA-4 but not PD-1 blockade attributed to favorable changes in immune landscape. CONCLUSIONS: Analysis of tumor-immune landscape in MDS during immunotherapy provides clinical response biomarkers

Metabolism of the dual FLT-3/Aurora kinase inhibitor CCT241736 in preclinical and human in vitro models: Implication for the choice of toxicology species.

CCT241736 is a dual fms-like tyrosine kinase 3 (FLT3)/Aurora kinase inhibitor in development for the treatment of acute myeloid leukaemia. The successful development of any new drug relies on adequate safety testing including preclinical toxicology studies. Selection of an appropriate preclinical species requires a thorough understanding of the compound's metabolic clearance and pathways, as well as other pharmacokinetic and pharmacodynamic considerations. In addition, elucidation of the metabolising enzymes in human facilitates improved clinical prediction based on population pharmacokinetics and can inform drug-drug interaction studies. Intrinsic clearance (CLint) determination and metabolite profiling of CCT241736 in human and four preclinical species (dog, minipig, rat and mouse) was undertaken in cryopreserved hepatocytes and liver microsomes. Recombinant human cytochrome P450 bactosomes (rCYP) were utilised to provide reaction phenotyping data and support prediction of metabolic pathways. CCT241736 exhibited low CLint in both hepatocytes and liver microsomes of human, dog, minipig and rat, but considerably higher CLint in mouse. CYP3A4 and CYP3A5 were identified as the major enzymes responsible for biotransformation of CCT241736 in human, exclusively forming five out of seven metabolites. Minipig showed greatest similarity to human with regard to both overall metabolic profile and abundance of specific metabolites relative to parent compound, and is therefore proposed as the most appropriate toxicological species. The greatest disparity was observed between human and dog. Based on metabolic profile, either mouse or rat is a suitable rodent species for toxicology studies

Myeloablative Fractionated Busulfan for Allogeneic Stem Cell Transplant in Older Patients or Patients With Comorbidities

Traditional conditioning regimens for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) provide suboptimal outcomes, especially for older patients and those with comorbidities. We hypothesized that a fractionated myeloablative busulfan dose delivered over an extended period would reduce nonrelapse mortality (NRM) while retaining antileukemic effects. Here, we performed a phase 2 trial for adults with hematological malignancies receiving matched related or unrelated allo-HCT. Participants received busulfan 80 mg/m2 as outpatients on days -20 and -13 before transplant. Fludarabine 40 mg/m2 was administered on days -6 to -3, followed by busulfan dosed to achieve a target area under the curve of 20 000 mol/min for the whole course. The primary end point was day-100 NRM. Seventy-eight patients were included, with a median age of 61 years (range, 39-70 years), who received transplantation for acute leukemia (24%), myelodysplastic syndrome (27%), or myeloproliferative disease/chronic myeloid leukemia (44%). HCT-specific comorbidity index (HCT-CI) was ≥3 in 34 (44%). With a median follow-up of 36.4 months (range, 2.9-51.5), the 100-day, 1-year, and 3-year NRM rates were 3.8%, 8%, and 9.3%, respectively, without a significant difference in age or HCT-CI score. The 1-year and 3-year relapse incidence was 10% and 18%, respectively. The 3-year overall survival was 80%, without a significant difference in age or HCT-CI score and was similar for patients aged \u3e60 years and those aged \u3c60 years as well as for those with HCT-CI ≥3 and HCT-CI \u3c3. Overall, a myeloablative fractionated busulfan regimen has low NRM without an increase in relapse rate, resulting in promising survival, even in older patients or in patients with comorbidities. This trial was registered at www.clinicaltrials.gov as #NCT02861417

Haploidentical versus Matched Unrelated versus Matched Sibling Donor Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide

With the use of post-transplantation cyclophosphamide (PTCy), the outcomes of mismatched related donor hematopoietic cell transplantation (HCT) are now approaching those of matched donor HCT. Here we compared haploidentical donor HCT versus HLA-matched unrelated donor (MUD) HCT and HLA-identical sibling donor (MSD) HCT in a cohort in which all patients received PTCy for graft-versus-host disease (GVHD) prophylaxis. We included 661 patients (275 haploidentical, 246 MUD, and 140 MSD HCT). The most common diagnoses were acute myelogenous leukemia and myelodysplastic syndrome. In multivariate analysis, the haploidentical group was found to have significantly higher nonrelapse mortality (NRM) (hazard ratio [HR], 3.2; 95% confidence interval [CI], 2 to 4.9; P \u3c .001) and inferior progression-free survival (HR, 1.8; 95% CI, 1.4 to 2.4; P \u3c .001) and overall survival (OS; HR, 2.2; 95% CI, 1.6 to 3; P \u3c .001) compared with the MUD group. Relapse was the most common cause of death in all groups. Among causes of NRM, the haploidentical group had more infection-related deaths and fewer GVHD-related deaths than the other groups. The haploidentical group also had a higher risk of viral and fungal infections, grade ≥3 hemorrhagic cystitis, and cardiovascular toxicities and slower reconstitution of CD4, CD8, and regulatory T cells but faster reconstitution of natural killer cells. In an exploratory analysis, older patients with older donors (\u3e50 years for both) appeared to have particularly high NRM and lower OS in the haploidentical group compared with the other groups. Our data suggest that even with the use of PTCy, the outcomes of haploidentical HCT are inferior to those of HLA-matched donor HCT

HLA Factors versus Non-HLA Factors for Haploidentical Donor Selection

When multiple haploidentical donors are available for transplantation, those of younger generations are generally selected over those of older generations. However, it is unclear who is the optimal donor when selecting candidates from within a generation, such as father versus mother, son versus daughter, or brother versus sister. Although traditionally male donors are favored over female donors, particularly for male recipients, and significant associations of individual HLA mis(matches) on outcomes are being increasingly recognized, the hierarchy of factors for donor selection is indeterminate. To assess whether HLA factors take precedence over non-HLA factors and to isolate the influence of specific characteristics on outcomes, we analyzed 412 patients stratified by donor relationship: child donor (son [n = 202] versus daughter [n = 96]), parent (father [n = 28] versus mother [n = 29]), and sibling (noninherited maternal [NIMA; n = 29] versus paternal [NIPA; n = 28] mismatched). Among siblings, NIMA mismatch was associated with a lower risk of acute graft-versus-host disease (aGVHD); B-leader mismatch was associated with high nonrelapse mortality (NRM), poor progression-free survival, and a trend toward poor overall survival (OS), whereas A-mismatch was associated with lower aGVHD. Among parent donors, the relationship did not impact any outcome; B-leader mismatch was associated with higher NRM and a trend toward poor OS, whereas A-mismatch was associated with lower NRM and improved progression-free survival and OS. Among child donors, no individual HLA mismatch was predictive of any outcome, and daughter donors were not associated with any adverse outcomes in multivariate analyses. Our data suggest that certain HLA factors may be more significant in some cases and should be given priority over simply selecting a donor based on relationship/sex

Preconception Care in International Settings

Objectives: This literature review briefly describes international programs, policies, and activities related to preconception care and resulting pregnancy outcomes. Methods: Electronic databases were searched and findings supplemented with secondary references cited in the original articles as well as textbook chapters, declarations, reports, and recommendations. Results: Forty-two articles, book chapters, declarations, and other published materials were reviewed. Policies, programs, and recommendations related to preconceptional health promotion exist worldwide and comprise a readily identifiable component of historic and modern initiatives pertaining to women's health, reproductive freedom, and child survival. Conclusions: The integration of preconception care services within a larger maternal and child health continuum of care is well aligned with a prevention-based approach to enhancing global health